SERCA2 protects against cisplatin-induced damage of auditory cells: Possible relation with alleviation of ER stress.

AIMS: SERCA2, one of the P-type pumps encoded by gene ATP2A2, is the only calcium reflux channel of the endoplasmic reticulum (ER) and participates in maintaining calcium homeostasis. The present study was designed to explore SERCA2 expression pattern in auditory hair cells and the possible mechanism underlying the effects of SERCA2 on cisplatin-induced ototoxicity. MAIN METHODS: The SERCA2 expression pattern in cochlea hair cells and HEI-OC1 cells was measured by Western blot (WB) and immunofluorescence staining. The apoptosis and its related factors were detected by TUNEL assay and WB. The expression levels of ER stress-related factors, ATF6, PERK, IRE1α, and GRP78, were measured via WB. As for the determination of SERCA2 overexpression and knockdown, plasmids and lentiviral vectors were constructed, respectively. KEY FINDINGS: We found that SERCA2 was highly expressed in cochlea hair cells and HEI-OC1 cells. Of note, the level of SERCA2 expression in neonatal mice was remarkably higher than that in adult mice. Under the exposure of 30 µM cisplatin, SERCA2 was down-regulated significantly compared with the control group. In addition, cisplatin administration triggered the occurrence of ER stress and apoptosis. Those events were reversed by overexpressing SERCA2. On the contrary, SERCA2 knockdown could aggravate the above processes. SIGNIFICANCE: The findings from the present study disclose, for the first time, that SERCA2 is abundantly expressed in cochlea hair cells, and the suppression of SERCA2 caused by cisplatin could trigger ER homeostasis disruption, thereby implying that SERCA2 might be a promising target to prevent cisplatin-induced cytotoxicity of hair cells.

Calcium channel inhibitor and extracellular calcium improve aminoglycoside-induced hair cell loss in zebrafish.

Aminoglycosides are commonly used antibiotics for treatment of gram-negative bacterial infections, however, they might act on inner ear, leading to hair-cell death and hearing loss. Currently, there is no targeted therapy for aminoglycoside ototoxicity, since the underlying mechanisms of aminoglycoside-induced hearing impairments are not fully defined. This study aimed to investigate whether the calcium channel blocker verapamil and changes in intracellular & extracellular calcium could ameliorate aminoglycoside-induced ototoxicity in zebrafish. The present findings showed that a significant decreased number of neuromasts in the lateral lines of zebrafish larvae at 5 days' post fertilization after neomycin (20 µM) and gentamicin (20 mg/mL) exposure, which was prevented by verapamil. Moreover, verapamil (10-100 µM) attenuated aminoglycoside-induced toxic response in different external calcium concentrations (33-3300 µM). The increasing extracellular calcium reduced hair cell loss from aminoglycoside exposure, while lower calcium facilitated hair cell death. In contrast, calcium channel activator Bay K8644 (20 µM) enhanced aminoglycoside-induced ototoxicity and reversed the protective action of higher external calcium on hair cell loss. However, neomycin-elicited hair cell death was not altered by caffeine, ryanodine receptor (RyR) agonist, and RyR antagonists, including thapsigargin, ryanodine, and ruthenium red. The uptake of neomycin into hair cells was attenuated by verapamil and under high external calcium concentration. Consistently, the production of reactive oxygen species (ROS) in neuromasts exposed to neomycin was also reduced by verapamil and high external calcium. Significantly, zebrafish larvae when exposed to neomycin exhibited decreased swimming distances in reaction to droplet stimulus when compared to the control group. Verapamil and elevated external calcium effectively protected the impaired swimming ability of zebrafish larvae induced by neomycin. These data imply that prevention of hair cell damage correlated with swimming behavior against aminoglycoside ototoxicity by verapamil and higher external calcium might be associated with inhibition of excessive ROS production and aminoglycoside uptake through cation channels. These findings indicate that calcium channel blocker and higher external calcium could be applied to protect aminoglycoside-induced listening impairments.

Protective role of pyrroloquinoline quinone against gentamicin induced cochlear hair cell ototoxicity.

Gentamicin (GM) is one of the commonly used antibiotics in the aminoglycoside class but is ototoxic, which constantly impacts the quality of human life. Pyrroloquinoline quinone (PQQ) as a redox cofactor produced by bacteria was found in soil and foods that exert an antioxidant and redox modulator. It is well documented that the PQQ can alleviate inflammatory responses and cytotoxicity. However, our understanding of PQQ in ototoxicity remains unclear. We reported that PQQ could protect against GM-induced ototoxicity in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells in vitro. To evaluate reactive oxygen species (ROS) production and mitochondrial function, ROS and JC-1 staining, oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) measurements in living cells, mitochondrial dynamics analysis was performed. GM-mediated damage was performed by reducing the production of ROS and inhibiting mitochondria biogenesis and dynamics. PQQ ameliorated the cellular oxidative stress and recovered mitochondrial membrane potential, facilitating the recovery of mitochondrial biogenesis and dynamics. Our in vitro findings improve our understanding of the GM-induced ototoxicity with therapeutic implications for PQQ.

Ezetimibe protects against Gentamycin-induced ototoxicity in rats by antioxidants, anti-inflammatory mechanisms, and BDNF upregulation.

OBJECTIVE: The threat of hearing loss has become a universal reality. Gentamycin (GM) can lead to ototoxicity and may result in permanent hearing loss. This study aimed to elucidate whether the hypolipidemic drug Ezetimibe (EZE) has a possible underlying mechanism for protecting rats from GM-induced ototoxicity. METHODS AND RESULTS: 30 male Wister albino rats were separated into three groups, ten in each group: control, GM, and GM + EZE. At the end of the experiment, rats underwent hearing threshold evaluation via auditory brainstem response (ABR), carotid artery blood flow velocity (CBV), and resistance (CVR) measurement, in addition to a biochemical assessment of serum malondialdehyde (MDA), nitric oxide (NO), catalase (CAT), hemeOxygenase-1 (HO-1), and tumor necrosis factor-α (TNF-α). Also, real-time PCR was employed to quantify the levels of brain-derived neurotrophic factor (BDNF). Cochlea was also studied via histological and immunohistochemical methods. GM revealed a significant increase in CVR, MDA, NO, and TNF-α and a significant decrease in ABR, CBV, CAT, HO-1, and cochlear BDNF expression. EZE supplementation revealed a significant rise in ARB in addition to CBV and a decline in CVR and protected cochlear tissues via antioxidant, anti-inflammatory, and antiapoptotic mechanisms via downregulating Caspase-3 immunoreaction, upregulating proliferating cellular nuclear antigen (PCNA) immunoreaction, and upregulating of the cochlear BDNF expression. Correlations were significantly negative between BDNF and MDA, NO, TNF-α, COX 2, and caspase-3 immunoreaction and significantly positive with CAT, HO-1, and PCNA immunoreaction. DISCUSSION: EZE can safeguard inner ear tissues from GM via antioxidant, anti-inflammatory, and antiapoptotic mechanisms, as well as upregulation of BDNF mechanisms.

Prevention and treatment of cisplatin-induced ototoxicity in adults: A systematic review.

OBJECTIVES: Ototoxicity is a common disabling side effect of platinum-based chemotherapy. This study aimed to assess the evidence on the management of platinum-induced ototoxicity in adult cancer patients. METHODS: Four databases were searched up to 1 November 2022. Original studies were included if they reported on a pharmacologic or non-pharmacologic intervention to prevent or treat platinum ototoxicity in adults. The articles' quality was assessed via two grading scales. RESULTS: Nineteen randomised controlled trials and five quasi-experimental studies with 1673 patients were analysed. Eleven interventions were identified, nine pharmacological and two non-pharmacological. Six of the interventions (sodium thiosulphate, corticoids, sertraline, statins, multivitamins and D-methionine) showed mild benefits in preventing cisplatin-induced ototoxicity. Only one trial assessed corticoids as a potential treatment. Overall, only six trials were deemed with a low risk of bias. The majority of studies inadequately documented intervention-related adverse effects, thereby limiting safety conclusions. CONCLUSIONS: Current interventions have mild benefits in preventing cisplatin-induced ototoxicity in adult cancer patients. Sodium thiosulphate is the most promising intervention as a preventive strategy. Rigorous, high-quality research is warranted, encompassing an evaluation of all potential symptoms and innovative treatment modalities.

Gstm1/Gstt1 is essential for reducing cisplatin ototoxicity in CBA/CaJ mice.

Cisplatin is a widely used chemotherapeutic agent. However, its clinical utility is limited because of cisplatin-induced ototoxicity. Glutathione S-transferase (GST) was found to play a vital role in reducing cisplatin ototoxicity in mice. Deletion polymorphisms of GSTM1 and GSTT1, members of the GST family, are common in humans and are presumed to be associated with cisplatin-induced hearing impairment. However, the specific roles of GSTM1 and GSTT1 in cisplatin ototoxicity are not completely clear. Here, under cisplatin treatment, simultaneous deletion of Gstm1 and Gstt1 lead to a more profound hearing loss in CBA/CaJ mice (Gstm1/Gstt1-DKO) than in wild-type mice. The Gstm1/Gstt1-DKO mice, in which phase II detoxification genes were upregulated, exhibited more severe oxidative stress and higher outer hair cell apoptosis in the cochleae than the control mice. Thus, our study revealed that Gstm1 and Gstt1 protect auditory hair cells from cisplatin-induced ototoxicity in the CBA/CaJ mice, and genetic screening for GSTM1 and GSTT1 polymorphisms could help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.

Tetramethylpyrazine Attenuates Radiation-Induced Ototoxicity in a Rat Model.

INTRODUCTION: Tetramethylpyrazine (TMP) is a chemical compound, which has been shown to possess numerous biological features such as anticoagulation, inhibition of platelet aggregation, anti-inflammation, capillary dilatation, improvement in microcirculation, and protection against reactive oxygen radicals. The aim of the present study was to investigate the protective effect of TMP against radiation-induced ototoxicity. MATERIALS AND METHODS: 40 rats were divided into four groups. The first group was irradiated for 5 days. The second group received a single dose of 140 mg/kg/day intraperitoneal TMP given to the rats 30 min before radiotherapy (RT) for 5 days. The third group received a single dose of 140 mg/kg/day i.p. TMP for 5 days, whereas the fourth group was administered saline. All rats underwent distortion product otoacoustic emission (DPOAE) and auditory brainstem response measurements before and after the application. The temporal bulla of animals was removed for immunohistopathological examination. RESULTS: Signal-noise ratio values were significantly decreased in the RT group for the frequencies of 2-32 kHz after RT (p < 0.05), whereas the difference was not significant in terms of pre- and posttreatment values for the other groups. Also in the RT group, the ABR thresholds were significantly increased after treatment. In H&E staining, the mean scores for outer hair cells (OHCs), stria vascularis (SV), and spiral ganglion (SG) injuries were significantly higher in RT and RT + TMP groups than in the other groups. The mean OHCs and SV injury scores were also significantly higher in the RT group than in the RT + TMP group (p < 0.05). The number of cochleas that showed cytoplasmic caspase-3 immunoreactivity in the OHC, SV, and SG was significantly higher in RT and RT + TMP groups than in the other groups. CONCLUSION: The findings of the present study suggest that TMP may have a therapeutic potential for preventing sensorineural hearing loss (SNHL) related to RT.

3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) protects hair cells from cisplatin-induced ototoxicity in vitro: possible relation to the activities of p38 MAPK signaling pathway.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) gene encodes rate-limiting enzyme in cholesterol biosynthesis, which is related to cell proliferation and mitochondrial function. The present study was designed to explore the expression of HMGCR in murine cochlear hair cells and HEI-OC1 cells and the possible mechanisms underpinning the actions of HMGCR in cisplatin-induced ototoxicity, with special attention given to p38 mitogen-activated protein kinase (MAPK) activities in vitro. The expressions of HMGCR, p-p38, cleaved caspase-3 and LC3B was measured by immunofluorescence and western blot. JC-1 staining and MitoSOX Red were used to detect mitochondria membrane potential (MMP) and reactive oxygen species (ROS) levels respectively. The apoptosis of auditory cells was assessed by TUNEL staining and flow cytometry. Protein levels of bcl2/bax and beclin1 were examined by western blot. We found that HMGCR was widely expressed in the auditory cells, of both neonatal mice and 2-month-old mice, in cytoplasm, nucleus and stereocilia. Moreover, 30 µM cisplatin elicited the formation of ROS, which, in turn, led to HMGCR reduction, activating p38 kinase-related apoptosis and autophagy in auditory cells. Meanwhile, co-treatment with ROS scavenger at a concentration of 2 mM, N-acetyl-L-cysteine (NAC), could alleviate the aforementioned changes. In addition, HMGCR silencing resulted in higher p38 MAPK-mediated apoptosis and autophagy under cisplatin injury. Taken together, we demonstrate that, for the first time, that HMGCR is expressed in the cochlear. Furthermore, HMGCR exerts protective benefit on auditory cells against cisplatin-mediated injury stimulated by ROS, culminating in regulation of p38 MAPK-dependent apoptosis and autophagy.

SIRT3/GLUT4 signaling activation by metformin protect against cisplatin-induced ototoxicity in vitro.

Cisplatin is highly effective for killing tumor cells. However, as one of its side effects, ototoxicity limits the clinical application of cisplatin. The mechanisms of cisplatin-induced ototoxicity have not been fully clarified yet. SIRT3 is a deacetylated protein mainly located in mitochondria, which regulates a variety of physiological processes in cells. The role of SIRT3 in cisplatin-induced hair cell injury has not been founded. In this study, primary cultured cochlear explants exposed to 5 µM cisplatin, as well as OC-1 cells exposed to 10 µM cisplatin, were used to establish models of cisplatin-induced ototoxicity in vitro. We found that when combined with cisplatin, metformin (75 µM) significantly up-regulated the expression of SIRT3 and alleviated cisplatin-induced apoptosis of hair cells. We regulated the expression of SIRT3 to explore the role of SIRT3 in cisplatin-induced auditory hair cell injury. Overexpression of SIRT3 promoted the survival of auditory hair cells and alleviated the apoptosis of auditory hair cells. In contrast, knockdown of SIRT3 impaired the protective effect of metformin and exacerbated cisplatin injury. In addition, we found that the protective effect of SIRT3 may be achieved by regulating GLUT4 translocation and rescuing impaired glucose uptake caused by cisplatin. Our study confirmed that upregulation of SIRT3 may antagonize cisplatin-induced ototoxicity, and provided a new perspective for the study of cisplatin-induced ototoxicity.

Apelin-13 protects against cisplatin-induced ototoxicity by inhibiting apoptosis and regulating STAT1 and STAT3.

The ototoxic side effect of cisplatin is a main cause of sensorineural hearing loss. This side effect limits the clinical application of cisplatin and affects patients' quality of life. This study was designed to investigate the effect of apelin-13 on cisplatin-induced C57BL/6 mice hearing loss model and explore the potential underlying molecular mechanisms. Mice were intraperitoneally injected with 100 µg/kg apelin-13 2 h before 3 mg/kg cisplatin injection for 7 consecutive days. Cochlear explants cultured in vitro were pretreated with 10 nM apelin-13 2 h prior to 30 µM cisplatin treatment for another 24 h. Hearing test and morphology results showed that apelin-13 attenuated cisplatin-induced mice hearing loss and protected cochlear hair cells and spiral ganglion neurons from damage. In vivo and in vitro experimental results showed that apelin-3 reduced cisplatin-induced apoptosis of hair cells and spiral ganglion neurons. In addition, apelin-3 preserved mitochondrial membrane potential and inhibited ROS production in cultured cochlear explants. Mechanistic studies showed that apelin-3 decreased cisplatin-induced cleaved caspase 3 expression but increased Bcl-2; inhibited the expression of pro-inflammatory factors TNF-a and IL-6; and increased STAT1 phosphorylation but decreased STAT3 phosphorylation. In conclusion, our results indicate that apelin-13 could be a potential otoprotective agent to prevent cisplatin-induced ototoxicity by inhibiting apoptosis, ROS production, TNF-α and IL-6 expression, and regulating phosphorylation of STAT1 and STAT3 transcription factors.

Prevention and management of hearing loss in patients receiving ototoxic medications.

Following the efforts of patient advocates, the World Health Organization published updated guidelines for management of multidrug-resistant tuberculosis in 2018 that advised against the routine use of ototoxic second-line injectable drugs (amikacin, capreomycin and kanamycin). Although hearing loss is no longer considered an unavoidable harm for patients with multidrug-resistant tuberculosis, ototoxic medications continue to be used for several infectious and oncological disorders around the world. These drugs contribute to more than a half a million cases of hearing loss worldwide annually. Currently, there are no international standards for preventing and managing hearing loss associated with ototoxic medications. We present recent data on the prevention and management of hearing loss related to these drugs and highlight the variability in care across settings. More importantly, we aim to provide an evidence-based framework for evaluating, screening and preventing ototoxicity. Finally, we identify avenues for future research so that patients no longer have to choose between hearing loss and a disease cure. There remain significant gaps in our understanding about optimal screening and treatment of ototoxic hearing loss. Here we aim to inspire future international guidelines to address gaps in ototoxicity care and establish research agendas for eliminating ototoxic medications.

Sous l'impulsion des défenseurs des droits des patients, l'Organisation mondiale de la Santé a publié une version actualisée des lignes directrices relatives à la prise en charge de la tuberculose multirésistante en 2018, qui déconseille l'usage systématique de médicaments ototoxiques injectables de deuxième intention (amikacine, capréomycine et kanamycine). Bien que la perte auditive ne soit plus considérée comme un risque inévitable chez les patients atteints de tuberculose multirésistante, les médicaments ototoxiques continuent à être largement employés pour traiter de nombreuses maladies infectieuses et oncologiques à travers le monde. Ces médicaments sont impliqués chaque année dans plus de la moitié des cas de déficience auditive dans le monde. Il n'existe actuellement aucune norme internationale consacrée à la prévention et à la prise en charge de la perte auditive causée par des médicaments ototoxiques. Dans le présent document, nous exposons les données récentes à ce propos et soulignons la variabilité des soins prodigués d'une région à l'autre. Nous tentons surtout d'établir, à partir d'éléments concrets, un cadre dédié à l'évaluation, au dépistage et à la prévention de l'ototoxicité. Enfin, nous dégageons des pistes pour de futures études, afin que les patients n'aient plus à choisir entre une perte auditive et un remède. D'importantes lacunes subsistent dans notre compréhension du dépistage et du traitement de la perte auditive d'origine ototoxique. Nous espérons inspirer de futures lignes directrices internationales afin d'y remédier et de développer des programmes de recherche pour supprimer les médicaments ototoxiques.

Tras los esfuerzos de los defensores de pacientes, la Organización Mundial de la Salud publicó en 2018 unas directrices actualizadas para el tratamiento de la tuberculosis multirresistente en las que se desaconsejaba el uso rutinario de medicamentos inyectables de segunda línea ototóxicos (amikacina, capreomicina y kanamicina). Aunque la pérdida de audición ya no se considera un daño inevitable para los pacientes con tuberculosis multirresistente, los medicamentos ototóxicos se siguen administrando para varios trastornos infecciosos y oncológicos en todo el mundo. Estos fármacos contribuyen a más de medio millón de casos de pérdida de audición en todo el mundo cada año. En la actualidad, no existen estándares internacionales para prevenir y tratar la pérdida de audición asociada a los medicamentos ototóxicos. En este documento, se presentan datos recientes sobre la prevención y el tratamiento de la pérdida de audición relacionada con estos fármacos y se destaca la variabilidad de la atención en los distintos entornos. Además, se pretende ofrecer un marco basado en la evidencia para evaluar, detectar y prevenir la ototoxicidad. Por último, se identifican las vías de investigación futura para que los pacientes no tengan que elegir entre la pérdida de audición y la cura de la enfermedad. Siguen existiendo importantes deficiencias en el conocimiento del cribado y el tratamiento óptimos de la pérdida de audición ototóxica. En este sentido, se pretende inspirar futuras directrices internacionales para abordar las deficiencias en la atención a la ototoxicidad y establecer programas de investigación para eliminar los medicamentos ototóxicos.

Explore the effect of LLY-283 on the ototoxicity of auditory cells caused by cisplatin: A bioinformatic analysis based on RNA-seq.

BACKGROUND: Cisplatin is a commonly used chemotherapeutic drug in clinics, and long-term application will lead to hearing impairment. LLY-283, an inhibitor of PRMT5, has not been reported in deafness. Our study aimed to explore the mechanism of LLY-283 in hearing impairment. MATERIALS AND METHODS: First, we performed RNA-seq (cisplatin in the experimental group and DMSO in the control group) to obtain the biological processes mainly involved in differentially expressed genes (DEGs). CCK-8 and LDH experiments were used to observe the effect of LLY-283 on cisplatin-induced auditory cell injury. ROS experiment was used to monitor the impact of LLY-283 on oxidative damage of auditory cells. Effect of LLY-283 on apoptosis of auditory cells detected by TUNEL experiment. PCR and Western blotting were used to detect the expression of genes and proteins related to auditory cell apoptosis in LLY-283 cells. Meanwhile, we explored the effect of LLY-283 on the expression of PRMT5 in cisplatin-induced hearing impaired cells at RNA and protein levels. RESULTS: Biological process analysis showed that DEGs were mainly enriched in the apoptotic process involved in morphogenesis (-Log10 P = 3.71). CCK-8 and LDH experiments confirmed that LLY-283 could save cisplatin-induced auditory cell injury. ROS experiments confirmed that LLY-283 could rescue cisplatin-induced oxidative damage to auditory cells. TUNEL experiments confirmed that LLY-283 could protect cisplatin-induced apoptosis of auditory cells. Meanwhile, LLY-283 could inhibit the expression of PRMT5 in auditory cells induced by cisplatin. CONCLUSION: LLY-283 can rescue cisplatin-induced auditory cell apoptosis injury. LLY-283 can inhibit the increase in PRMT5 expression induced by cisplatin.

Oral D-methionine protects against cisplatin-induced hearing loss in humans: phase 2 randomized clinical trial in India.

Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.Design: Randomised parallel double-blind placebo-controlled exploratory Phase 2 study.Study samples: Fifty adult cancer patients received oral D-met or placebo before each cisplatin dose. Physical examination, blood collection and audiometry occurred at baseline and subsequent visits plus post-treatment audiometry. After attrition, final analysis included 27 patients.Results: Significant treatment group by ear and time (baseline vs. post-treatment) interactions occurred at 10 kHz and 11.2 kHz. Placebo and D-met groups differed in threshold shift for left ear at 11.2 kHz (mean difference = 22.97 dB [9.59, 36.35]). Averaging across ears, placebo group showed significant threshold shifts from baseline to post-treatment at 10 kHz (mean shift= -13.65 dB [-21.32,-5.98]), 11.2 kHz (-16.15 dB [-25.19,-7.12]), and 12.5 kHz (-11.46 dB [-19.18,-3.74]) but not 8 kHz (-8.65 dB [-17.86, 0.55]). The D-met group showed no significant threshold shifts (8 kHz: -1.25 dB [-7.75, 5.25]; 10 kHz:-3.93 dB [-8.89, 1.03]; 11.2 kHz:-4.82 dB [-11.21, 1.57]; 12.5 kHz:-3.68 dB [-11.57, 4.21]). Side effects did not significantly differ between groups.Conclusion: Oral D-met reduces cisplatin-induced ototoxicity in humans.

Progress in protecting vestibular hair cells.

Vestibular hair cells are mechanosensory receptors that are capable of detecting changes in head position and thereby allow animals to maintain their posture and coordinate their movement. Vestibular hair cells are susceptible to ototoxic drugs, aging, and genetic factors that can lead to permanent vestibular dysfunction. Vestibular dysfunction mainly results from the injury of hair cells, which are located in the vestibular sensory epithelium. This review summarizes the mechanisms of different factors causing vestibular hair cell damage and therapeutic strategies to protect vestibular hair cells.

Hair Cell Protection from Ototoxic Drugs.

Hearing loss is often caused by death of sensory hair cells (HCs) in the inner ear. HCs are vulnerable to some ototoxic drugs, such as aminoglycosides(AGs) and the cisplatin.The most predominant form of drug-induced cell death is apoptosis. Many efforts have been made to protect HCs from cell death after ototoxic drug exposure. These mechanisms and potential targets of HCs protection will be discussed in this review.And we also propose further investigation in the field of HCs necrosis and regeneration, as well as future clinical utilization.

Necroptosis and Apoptosis Contribute to Cisplatin and Aminoglycoside Ototoxicity.

Ototoxic side effects of cisplatin and aminoglycosides have been extensively studied, but no therapy is available to date. Sensory hair cells, upon exposure to cisplatin or aminoglycosides, undergo apoptotic and necrotic cell death. Blocking these cell death pathways has therapeutic potential in theory, but incomplete protection and lack of therapeutic targets in the case of necrosis, has hampered the development of clinically applicable drugs. Over the past decade, a novel form of necrosis, termed necroptosis, was established as an alternative cell death pathway. Necroptosis is distinguished from passive necrotic cell death, in that it follows a cellular program, involving the receptor-interacting protein kinase (RIPK) 1 and RIPK3. In this study, we used pharmacological and genetic interventions in the mouse to test the relative contributions of necroptosis and caspase-8-mediated apoptosis toward cisplatin and aminoglycoside ototoxicity. We find that ex vivo, only apoptosis contributes to cisplatin and aminoglycoside ototoxicity, while in vivo, necroptosis as well as apoptosis are involved in both sexes. Inhibition of necroptosis and apoptosis using pharmacological compounds is thus a viable strategy to ameliorate aminoglycoside and cisplatin ototoxicity.SIGNIFICANCE STATEMENT The clinical application of cisplatin and aminoglycosides is limited due to ototoxic side effects. Here, using pharmaceutical and genetic intervention, we present evidence that two types of programmed cell death, apoptosis and necroptosis, contribute to aminoglycoside and cisplatin ototoxicity. Key molecular factors mediating necroptosis are well characterized and druggable, presenting new avenues for pharmaceutical intervention.

The Protective Effect of Platelet Rich Plasma Against Cisplatin-Induced Ototoxicity.

Cisplatin, a pharmacological agent widely used for treating many cancers, may cause serious side effects including ototoxicity, nephrotoxicity, and peripheral neuropathy. The present study aimed to investigate whether platelet-rich plasma (PRP) protects against cisplatin ototoxicity. Eight rats (16 ears) were divided into 2 groups: control group (4 rats, 8 ears) that received intratympanic saline and study group (4 rats, 8 ears) that received intratympanic PRP. Cisplatin (10 mg/day intraperitoneally) or vehicle was administered 2 times per day to the animals. Auditory brainstem responses were recorded preoperatively and postoperatively on day 4 and at week 3. The authors compared the morphological appearances of spiral ganglion cells and the organ of Corti and the density of spiral ganglion cells between treatment groups. The number of outer hair cells in the organ of Corti significantly decreased in the control group compared with that in the PRP group. Although no statistically significant difference was observed between the groups regarding ABR thresholds on day 4 (P = 0.083, a statistically significant difference was observed between groups at week 3 (P = 0.038). Our results suggest that PRP can prevent cisplatin-induced ototoxicity.

Otoprotective Effect of 2,3,4',5-Tetrahydroxystilbene-2-O-ß-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-ß-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.

Otoprotective Effect of Cortexin, Cogitum, and Elkar Administered Simultaneously with Netromycin in the Experiment.

We studied possible otoprotective effect of drugs widely used for the correction of perinatal hypoxic brain damage in premature infants. The experiments were carried out on immature rabbits with an immature hearing organ. The auditory function was assessed by DPOAE and ABR methods in intact animals and rabbits treated with therapeutic doses of netromycin alone or in combination with the drugs that normalize metabolic processes in the brain (Cortexin, Cogitum, Elkar, vitamin B2, ATP, and cocarboxylase). It was found that the administered drugs produced an otoprotective effect and reduced the severity, but did not eliminate the ototoxic effect.

Recommendations for ototoxicity surveillance for childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCare Consortium.

Childhood, adolescent, and young adult (CAYA) cancer survivors treated with platinum-based drugs, head or brain radiotherapy, or both have an increased risk of ototoxicity (hearing loss, tinnitus, or both). To ensure optimal care and reduce consequent problems-such as speech and language, social-emotional development, and learning difficulties-for these CAYA cancer survivors, clinical practice guidelines for monitoring ototoxicity are essential. The implementation of surveillance across clinical settings is hindered by differences in definitions of hearing loss, recommendations for surveillance modalities, and remediation. To address these deficiencies, the International Guideline Harmonization Group organised an international multidisciplinary panel, including 32 experts from ten countries, to evaluate the quality of evidence for ototoxicity following platinum-based chemotherapy and head or brain radiotherapy, and formulate and harmonise ototoxicity surveillance recommendations for CAYA cancer survivors.